Although natural killer (NK) cells are best known for their capacity to kill tumor cells in a perforin-dependent manner, recent studies have also indicated an important role for NK cells in innate immunity to pathogens, especially viruses. In prior work, the applicant's laboratory has elucidated the basis for genetic resistance of certain strains of mice to murine cytomegalovirus (MCMV). This is due to a genetic locus in the NK gene complex (NKC) for an NK cell activation receptor that recognizes an MCMV encoded ligand. In vitro and in vivo studies have revealed two phases of NK cell responses during MCMV infection, a "non-specific" early phase followed by selective proliferation of NK cells bearing the relevant activation receptor. Available data from the literature and the applicant's laboratory strongly suggest that mouse NK cell responses to poxviruses (ectromelia virus, vaccinia virus) are highly related to their responses to MCMV, and involve both the non-specific early phase and a specific phase involving another NK cell activation receptor encoded in the NKC. Therefore, the applicant proposes the following specific aims to study: 1) The basic characteristics of the NK cell response to poxviruses; 2) Specific NK cell receptor triggering; 3) The role of NKG2D in poxvirus infections; and 4) Innate immune evasion by poxviruses. These studies will provide unique insight into the innate NK cell immune response to poxviruses.